KR890002163B1

KR890002163B1 - Process for the preparation of 1-p-carbamoyl-methylphenoxy-3-isopropylamino-2-propaneol

Info

Publication number: KR890002163B1
Application number: KR1019850007520A
Authority: KR
Inventors: 유응걸; 한정식
Original assignee: 재단법인 한국화학연구소; 채영복
Priority date: 1985-10-12
Filing date: 1985-10-12
Publication date: 1989-06-21
Also published as: KR870003971A

Abstract

1-P-carbamoylmethylphenoxy-3-isopropylamino-2-propaneol of formula (I) is prepared by, (a) dissolving p-hydroxyphenylacetateamid in the liq. solution of M(OH) (where, M is Na or K), (b) reacting the liq. solution with epichlorohydrin at 10-60≰C to produce 1-p- carbamoylmethylphenoxy-2,3-epoxy propane of formula (III), (c) reacting the cpd. of formula (III) not separated with isopropylamine at 40-90≰C.

Description

1-P-카르바모일메틸페녹시-3-이소프로필아미노-2-프로판올의 제조방법Method for preparing 1-P-carbamoylmethylphenoxy-3-isopropylamino-2-propanol

본 발명은 다음 일반식(Ⅰ)의 1-P-카르바모일메틸페녹시-3-이소프로필아미노-2-프로판올의 제조방법에 관한 것이다. 더 상세히 설명하면, P-히드록시페닐아세트 아미드를 일반식 M(OH)의 수용액에 용해시키고, 이를 에피클로로히드린과 반응시켜 1-P-카르바모일메틸페녹시-2,3-에폭시프로판을 얻은 후, 이를 분리하거나 또는 분리하지 않은 상태에서 이소프로필아민과 반응시켜 상기 일반식(Ⅰ)의 표제화합물을 제조하는 방법에 관한 것이다.The present invention relates to a method for preparing 1-P-carbamoylmethylphenoxy-3-isopropylamino-2-propanol of the following general formula (I). In more detail, P-hydroxyphenylacetamide is dissolved in an aqueous solution of general formula M (OH) and reacted with epichlorohydrin to react with 1-P-carbamoylmethylphenoxy-2,3-epoxypropane. After obtaining the present invention, the present invention relates to a method for preparing the title compound of the general formula (I) by reacting with isopropylamine in a separated or unseparated state.

상기 일반식(Ⅰ)화합물은 베타 차단제로서 작용하는 유용한 물질로서, 1969년 아이. 씨. 아이 회사에서 P-히드록시프로페닐아세트아미드를 피페리딘 촉매 존재하에서 에피클로로히드린과 반응시킨 다음, 이를 밀페용기에서 이소프로필아민과 반응시켜 최초로 합성하였다.(참조 : 영국특허제 12,850,38)The compound of general formula (I) is a useful substance acting as a beta-blocker. Seed. I-Company was first synthesized by reacting P-hydroxypropenylacetamide with epichlorohydrin in the presence of a piperidine catalyst and then with isopropylamine in a hermetic container (see UK Patent No. 12,850,38). )

본 발명자들은 상기 특허의 방법대로 실시해 본 결과, 수율이 20~30% 정도로 극히 저조하여 산업성 및 시장성에 있어서 문제로 되며, 이러한 결과 때문에 실제로 사용되지 못하고 있는 실정이다. 더욱이 상기 출원인은 상기 발명의 효용성이 없음을 알고, 이를 개량한 1975년에 일본에서 공개된 일본공개특허소 50-32135호를 보면 P-히드록시페닐아세트아미드를 1-이소프로필아제티딘-3-올과 반응시켜 합성하였으나 이 방법은 1-이소프로필아제티딘-3-올의 합성 수율이 낮아 전체 수율이 낮다.The present inventors conducted the method according to the above patent, and the yield is extremely low at about 20-30%, which is a problem in industrial and marketability, and this situation is not actually used. Furthermore, the applicant knows that there is no utility of the present invention, and Japanese Patent Laid-Open No. 50-32135 published in Japan in 1975 when the present invention is improved, shows that P-hydroxyphenylacetamide has 1-isopropylazetidine-3- Synthesis was carried out by reaction with ol, but this method is low in overall yield because of low synthesis yield of 1-isopropylazetidin-3-ol.

또한 1-P-카르바모일메틸페녹시-2,3-프로판디올을 톨루엔술폰산클로라이드와 반응시킨 다음 이소프로필아민과 반응시켜 합성한 방법이 개시되었으며(핀란드 특허 제51,744)또한 오타 세이야쿠사에서는 1-P-카르바모일메틸페녹시-2,3-프로판디올을 아황산디메틸과 반응시켜 디옥사티오란옥시드를 72%의 수율로 얻고, 이를 디메틸포름아미드 용매하에서 이소프로필아민과 반응시켜 81% 이수율로 목적 화합물을 얻었다)참고 : 일본 공개 특허소 58-103349호). 상기 두 방법들은 P-히드록시페닐아세트아미드로 부터 목적물을 얻는데 3단계를 거쳐야 하며 모두 수율이 낮아 비경제적이다.Also disclosed is a process synthesized by reacting 1-P-carbamoylmethylphenoxy-2,3-propanediol with toluenesulfonic acid chloride followed by isopropylamine (Finland Patent No. 51,744). -P-carbamoylmethylphenoxy-2,3-propanediol was reacted with dimethyl sulfite to give dioxathiolanoxide in 72% yield, which was reacted with isopropylamine in dimethylformamide solvent to 81% Yield yielded the target compound. Reference: Japanese Patent Application Laid-Open No. 58-103349). Both methods require three steps to obtain the desired product from P-hydroxyphenylacetamide, both of which are uneconomical with low yields.

따라서, 본 발명자들은 상기의 결점을 제거하고자, 예의 연구, 검토한 결과, 공정 및 경제성의 면에서 우수한 방법을 개발하고 본 발명에 이르게 되었다.Accordingly, the present inventors have intensively studied and examined the above-mentioned problems, and as a result, have developed a method that is excellent in terms of process and economic feasibility and leads to the present invention.

이하 본 발명을 상세히 설명한다.Hereinafter, the present invention will be described in detail.

본 발명은 P-히드록시페닐아세트아미드를 1~2배 몰량의 일반식 M(OH)(식중, M은 나트륨, 칼륨)의 수용액에 가하여 용해시킨후 에피클로로히드린과 10~60℃에서 교반하여 반응시킨 다음, 냉각시켜 중간체인 1-P-카르바모일메틸페녹시-2,3-에폭시프로판을 높은 수율로 얻을 수 있다. 이렇게하여 얻은 1-P-카르바모일메틸페녹시-2,3-에폭시프로판을 물에 현탁시키고 교반하면서 이소프로필아민과 40~90℃에서 반응시켜 최종 목적물인 1-P-카르바모일메틸페녹시-3-이소프로필아미노-2-프로판올을 높은 수율로 얻었다.In the present invention, P-hydroxyphenylacetamide is added to an aqueous solution of 1 to 2 times the molar amount of general formula M (OH) (wherein M is sodium and potassium) and dissolved, followed by stirring at 10 to 60 ° C. with epichlorohydrin. And then cooled to obtain the intermediate 1-P-carbamoylmethylphenoxy-2,3-epoxypropane in high yield. The 1-P-carbamoylmethylphenoxy-2,3-epoxypropane thus obtained was suspended in water and reacted with isopropylamine at 40 to 90 ° C. with stirring to give 1-P-carbamoylmethylphenoxy as the final target. Ci-3-isopropylamino-2-propanol was obtained in high yield.

상기 M(OH)의 화합물로는 수산화나트륨, 수산화칼륨, 바람직하기로는 수산화나트륨 수용액이다.The compound of M (OH) is sodium hydroxide, potassium hydroxide, preferably sodium hydroxide aqueous solution.

염기로서 작용하는 상기 화합물 M(OH)을 다량으로 사용하면 다른 반응물인 에피클로로히드린과 반응하여 원하는 방향의 반응성을 감소시킴과 동시에 비용을 증가시키는 결점이 되므로 출발물질인 P-히드록시페닐아세트아미드에 대해 1~2배 몰량을 사용하는 것이 바람직하다.Using a large amount of the compound M (OH), which acts as a base, reacts with epichlorohydrin, another reactant, to reduce the reactivity in a desired direction and to increase the cost, thereby making it a starting material, P-hydroxyphenylacet. Preference is given to using 1 to 2 molar amounts per amide.

또한 에피클로로히드린을 과량으로 사용하면 반응성은 증가하나 반응 후 이를 제거하여야 하는 불편이 있다.In addition, the use of epichlorohydrin in excess increases the reactivity, but there is a inconvenience to remove it after the reaction.

따라서 에피클로로히드린의 양은 1~3배의 양으로 사용하는 것이 바람직하다.Therefore, the amount of epichlorohydrin is preferably used in an amount of 1 to 3 times.

따라서 본 발명의 방법은 첫단계에서 저렴하고 쉽게 구할 수 있는 염기와 쉽게 구할 수 있는 P-히드록시페닐아세트아미드를 사용하여 수용액중에서 에피클로로히드린과 반응시켜 중간 생성물을 얻을 수 있으며, 이렇게하여 얻은 중간생성물을 분리하여 또는 분리하지 않은채, 이소프로필아민과 반응시켜 최종목적물을 85% 이상의 높은 수율로 얻을 수 있는 경제적인 방법을 제공하는데 목적이 있다.Therefore, the method of the present invention can be obtained by reacting with epichlorohydrin in an aqueous solution using an inexpensive and easily available base and easily available P-hydroxyphenylacetamide in the first step to obtain an intermediate product. The objective is to provide an economical way to obtain intermediates with high yields of more than 85% by reacting with isopropylamine with or without separating intermediates.

다음 실시예에서 본 발명의 제조방법을 구체적으로 설명하며, 이 실시예에 한정되어 있는 것은 아니다.In the following examples, the production method of the present invention will be described in detail, but the present invention is not limited thereto.

[실시예 1]Example 1

P-히드록시페닐아세트아미드 30.2g(0.2몰)을 1.0N-수산화나트륨 수용액 270ml에 가하여 완전히 용해시킨 다음 에피클로로히드린 37g(0.4몰)을 가하고 상온에서 교반 반응시켰다. 80분간 반응시킨 후 냉각하여 생성물을 침전시킨후 여과하고 물로 세척한 후 진공건조(60℃, 15mmHg)시켜 1-P-카르바모일메틸페녹시-2,3-에폭시프로판백색분말 39.6g(수율 95.7%)을 얻었다. 녹는점 163~166℃30.2 g (0.2 mol) of P-hydroxyphenylacetamide was added to 270 ml of 1.0 N aqueous sodium hydroxide solution to completely dissolve it, and 37 g (0.4 mol) of epichlorohydrin was added thereto, followed by stirring at room temperature. After reacting for 80 minutes, the precipitate was cooled, precipitated, filtered, washed with water, and dried in vacuo (60 ° C., 15 mmHg) to give 39.6 g of 1-P-carbamoylmethylphenoxy-2,3-epoxypropane white powder (yield). 95.7%). Melting Point 163 ~ 166 ℃

[실시예 2]Example 2

1-P-카르바모일메틸페녹시-2,3-에폭시프로판 15.6g(0.075몰)을 물 390ml에 가하고 교반하면서 이소프로필아민 133g을 가하였다. 반응기 내부 온도를 85℃로 유지하고 1.5시간 반응시킨 후 감압하에 과잉의 이소프로필아민과 용매를 제거하고 백색분말을 얻는다.15.6 g (0.075 mol) of 1-P-carbamoylmethylphenoxy-2,3-epoxypropane was added to 390 ml of water, and 133 g of isopropylamine was added with stirring. After maintaining the inner temperature of the reactor at 85 ° C and reacting for 1.5 hours, excess isopropylamine and solvent were removed under reduced pressure to obtain a white powder.

이것을 물로 재결정화하여 1-P-카르바모일메틸페녹시-3-이소프로필아미노-2-프로판올 18.1g (수율 90.0%)을 얻었다. 녹는점 144~146℃This was recrystallized from water to give 18.1 g (yield 90.0%) of 1-P-carbamoylmethylphenoxy-3-isopropylamino-2-propanol. Melting Point 144 ~ 146 ℃

[실시예 3]Example 3

P-히드록시페닐아세트아미드 15.1g(0.1몰)을 1.0N-수산화나트륨 수용액 120ml에 용해시키고, 에피클로로히드린 11.1g을 가하여 상온에서 3시간 교반하였다.15.1 g (0.1 mol) of P-hydroxyphenylacetamide was dissolved in 120 ml of 1.0 N aqueous sodium hydroxide solution, and 11.1 g of epichlorohydrin was added thereto, followed by stirring at room temperature for 3 hours.

이소프로필아민 186.2g과 증류수 350ml를 넣고 2시간 환류시켰다. 감압하에 과잉의 이소프로필아민과 용매일부를 제거한 후 냉수로 냉각시켜 침전을 완결시켰다.186.2 g of isopropylamine and 350 ml of distilled water were added and refluxed for 2 hours. Excess isopropylamine and a portion of the solvent was removed under reduced pressure, followed by cooling with cold water to complete the precipitation.

백색침전을 여과하고, 포화소금 수용액으로 세척한 다음 감압조건기에서 건조시켰다. 증류수로 재결정화하여 목적물 22.9g(수율 86.1%)을 얻었다.The white precipitate was filtered, washed with saturated aqueous salt solution and dried under reduced pressure. Recrystallization from distilled water afforded 22.9 g (yield 86.1%) of the title compound.

[실시예 4]Example 4

P-히드록시페닐아세트아미드 30.2g(0.2몰)을 1.0N-수산화칼륨수용액 270ml에서 에피클로로히드린 37g(0.4 몰)과 실시예 1에서와 같은 조건에서 반응시켜 1-P-카르바모일메틸페녹시-2,3-에폭시프로판올 39.7g(수율 96.1%)얻었다. 녹는점 163~166℃30.2 g (0.2 mol) of P-hydroxyphenylacetamide was reacted with 37 g (0.4 mol) of epichlorohydrin in 270 ml of 1.0 N aqueous potassium hydroxide solution under the same conditions as in Example 1 to 1-P-carbamoylmethyl 39.7 g (96.1% yield) of phenoxy-2,3-epoxypropanol were obtained. Melting Point 163 ~ 166 ℃

[실시예 5]Example 5

P-히드록시페닐아세트아미드 15.1g(0.1몰)을 1.0N-수산화칼륨 수용액 120ml에서 실시예 3과 같은 조건하에서 반응시켜 1-P-카르바모일메틸페녹시-3-이소프로필아미노-2-프로판올 23.5g(수율 88.2%)을 얻었다.15.1 g (0.1 mole) of P-hydroxyphenylacetamide was reacted in 120 ml of 1.0 N-potassium hydroxide aqueous solution under the same conditions as in Example 3 to 1-P-carbamoylmethylphenoxy-3-isopropylamino-2- 23.5 g (88.2% yield) of propanol were obtained.

녹는점 144~146℃Melting Point 144 ~ 146 ℃

1H-NMR(CDO₃OD) : σ7.2~6.8(4H, 방향족),1 H-NMR (CDO ₃ OD): σ7.2 to 6.8 (4H, aromatic),

Claims

P-히드록시페닐아세트아미드와 에피클로로히드린 및 이소프로필아민과 반응시켜 1-P-카르바모일에틸페녹시-3-이소프로필아미노-2-프로판올을 제조함에 있어서, 하기 일반식(Ⅱ)의 P-히드록시페닐아세트아미드를 일반식 M(OH)(식중, M은 나트륨, 칼륨)의 수용액에 용해시키고, 에피클로로히드린과 10~60℃에서 반응시켜 일반식(Ⅲ)의 1-P-카르바모일메틸페녹시-2,3-에폭시프로판을 얻고 이를 분리 또는 분리하지 않은 상태로 이소프로필아민과 40~90℃에서 반응시켜 하기 일반식(Ⅰ)의 1-P-카르바모일메틸페녹시-3-이소프로필아미노-2-프로판올의 제조방법.In preparing 1-P-carbamoylethylphenoxy-3-isopropylamino-2-propanol by reacting P-hydroxyphenylacetamide with epichlorohydrin and isopropylamine, the following general formula (II) P-hydroxyphenylacetamide was dissolved in an aqueous solution of the general formula M (OH) (wherein M is sodium and potassium) and reacted with epichlorohydrin at 10 to 60 캜 to form 1- of general formula (III). P-carbamoylmethylphenoxy-2,3-epoxypropane was obtained and reacted with isopropylamine at 40-90 ° C. with or without separation of 1-P-carbamoyl of the general formula (I) Method for preparing methylphenoxy-3-isopropylamino-2-propanol.

제1항에 있어서, 일반식 M(OH)의 양이 P-히드록시페닐아세트아미드의 양에 대하여 1~2배몰 양을 사용함을 특징으로 하는 방법.The method according to claim 1, wherein the amount of the general formula M (OH) is used in an amount of 1-2 moles relative to the amount of P-hydroxyphenylacetamide.

제1항에 있어서, 용매로서 물을 사용하는 것이 특징인 방법.The method of claim 1 wherein water is used as the solvent.